Differential Immunotoxicity Induced by Two Different Windows of Developmental Trichloroethylene Exposure

Abstract

Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE) from gestational day (GD) 0 to postnatal day (PND) 49 alters several aspects of CD4+ T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0)) and early-life only (PND0-PND49). The mice were examined for specific alterations in CD4+ T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4+ T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4+ T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences.

Inflammatory and oxidative stress-related effects associated with neurotoxicity are maintained after exclusively prenatal trichloroethylene exposure

“…Gestational exposure to TCE in MRL+/+ mice has been described in detail (Blossom et al, 2008; Gilbert et al, 2014). Pregnant females were assigned to 3 groups by stratified randomization and given ultrapure water with 0 (control), 0.01, or 0.1 mg/ml TCE (purity 99+% purchased from Sigma, St. Louis, MO).…”

“…Children exposed to TCE beginning in utero to a TCE-contaminated water supply had altered ratios of T cell subsets indicating T cell hyperactivity (Byers et al, 1988). We and others have shown that TCE promoted expansion of activated/memory CD4 + T cells with a Th1-like pro- inflammatory phenotype (Peden-Adams et al, 2006; Blossom and Doss, 2007; Blossom et al, 2008; Gilbert et al, 2014). In terms of neurotoxicity, studies by our lab and others have shown cerebellar and hippocampal neurotoxicity with exposure during the perinatal and postnatal periods of development associated with decreased learning and increased locomotor and exploratory activity (Blossom et al, 2012; Blossom et al, 2013; Taylor et al, 1985; Isaccson et al, 1990).…”

Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease

“…We and others have shown that continuous developmental exposure to TCE in mice (gestation, lactation, and early life) generated CD4 + Tcell alterations and/or early signs of tissue inflammation in both normal and autoimmune-susceptible mouse strains [58,59]. Similar immune-altering effects were observed with gestation- or postnatal-only exposure in young adult mice [60,61]. We recently reported continuous chronic exposure to low-level TCE beginning at gestation generated autoimmune hepatitis at postnatal day 259 even when TCE exposure was stopped 15 weeks earlier [62].…”

Epigenetic toxicity of trichloroethylene: a single-molecule perspective

“…6), consistent with the recent report. 28 Based on this line of results, we deduced that the strong demethylation effect by TCE was the outcome from a co-operation among metabolic shift of cysteine, Dnmt detachment, and Tet reactivation. Considering the fact that Dnmt3a prefers to localize at heterochromatin from where the majority of non-coding RNAs are transcribed, we chose to screen the promoter methylation levels for a group of cancer-related miRNAs.…”